| Autor: |
Richard Gorlick, Edward A. Kolb, Malcolm A. Smith, Peter J. Houghton, Raushan T. Kurmasheva, Gemma Mudd, Johanna Lahdenranta, Philip Huxley, Tara Gelb, Stephen W. Erickson, Eric J. Earley, Alexander J. Lazar, Jing Wang, Sankaranarayanan Kannan, Sylvester Jusu, Zhaohui Xu, Douglas J. Harrison, Jonathan D. Gill, Michael E. Roth, Pooja Hingorani, Rossana Lazcano, Zhongting Zhang, Wendong Zhang, Xiangjun Tian, Yifei Wang |
| Rok vydání: |
2023 |
| Popis: |
Immunoconjugates targeting cell-surface antigens have demonstrated clinical activity to enable regulatory approval in several solid and hematologic malignancies. We hypothesize that a rigorous and comprehensive surfaceome profiling approach to identify osteosarcoma-specific cell-surface antigens can similarly enable development of effective therapeutics in this disease. Herein, we describe an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. Using this approach, we identified targets that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Furthermore, we tested BT1769, an MT1-MMP–targeted Bicycle toxin conjugate, in osteosarcoma patient-derived xenograft models. The results showed that BT1769 had encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that our approach identifies novel targets with significant therapeutic potential in osteosarcoma. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
